SOA Archives of Pharmacy & Pharmacology Review Article Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction This article was published in the following Scient Open Access Journal: SOA Archives of Pharmacy & Pharmacology Received September 20, 2018; Accepted October 01, 2018; Published October 08, 2018 Michel Bourin* Abstract Department of pharmacology, University of Nantes, 98, rue Joseph Blanchart 44100 Nantes, France The drugs active on erectile dysfunction in humans are now mainly phosphodiesterase 5 inhibitors, those that are marketed are Sildenafil, Vardefanil, Taladafil, and Avanafil. We propose a synthesis of the pharmacological, pharmacokinetic and clinical properties of these derivatives. We have also listed their most common side effects and their potential drug interactions. Keywords: Phosphodiesterase 5 inhibitors, Sildenafil, Vardefanil, Taladafil, Avanafil. Introduction Phosphodiesterase 5 (PDE 5) inhibitors are a type of targeted therapy used to treat people with pulmonary hypertension (PH) [1]. Targeted therapies slow the progression of PH and may even reverse some of the damage to the heart and lungs. There are two typesPDE of PDE5 inhibitors 5 inhibitor are currentlyalso used usedto treat to treat erectile PH: dysfunction sildenafil, tadalafil [3]. This [2]. is because the body has the same type of cells in the blood vessels of the lungs as the blood vessels of the penis. Viagra (sildenafil) has been used to treat erectile problems since 1998. to obtain or maintain an erection. These problems are common and can be solved effectivelyIn case byof erectileconsulting dysfunction a doctor itand is essential following to a determine suitable treatment. the cause ofUnless the difficulties there are more serious causes of erectile dysfunction, the recommended treatment will usually be a PDE5 inhibitor. PDE5 inhibitors are a particularly effective type of drug treatment, minimallyWhat is ainvasive PDE5 (oral Inhibitor? dosage), with a low risk of side effects. PDE 5 inhibitors block a particular enzyme (phosphodiesterase type 5), found in blood vessel walls [4]. PDE5 helps control blood flow to the pulmonary arteries. By stopping PDE5 from working, PDE 5 inhibitors (sildenafil and tadalafil) cause the blood vessels to relax. This increases blood flow to the lungs and lowers blood pressure. than 70% of patients with erectile dysfunction. These PDE5 inhibitors can be used to With PDE5 inhibitors, it is possible to restore the natural erectile response in more treatSexual all types stimulation of impotence, stimulates regardless the ofrelease the cause of NO of the by disorder.the endothelium and non- noradrenergic, non-cholinergic (NANC) parasympathetic fibers (rich in neuronal NOS) [5]. The NO diffuses cavernous bodies through the smooth fibers and binds to the hemic fraction of soluble guanylate cyclase, which stimulates cyclic GMP synthesis (cGMP). This cGMP is an important messenger in calcium signal transduction in the smooth fibers of cavernous bodies. CGMP reduces free sarcoplasmic calcium levels by binding to a cGMP-dependent protein kinase and a cGMP-dependent calcium channel [6]. This decrease in calcium promotes the relaxation of the smooth fibers of the arteries and cavernous bodies, allowing the expansion of sinusoidal spaces and erection. By inhibiting PDE5, the enzyme responsible for cGMP catabolism, sildenafil increases NO. *Corresponding Author: Michel Bourin, Department the absence of this stimulation [7]. of pharmacology, University of Nantes, 98, rue Since sexual stimulation is necessary to initiate NO release, sildenafil is ineffective in Joseph Blanchart 44100 Nantes, France, Email: PDE5 is the predominant isoform of phosphodiesterase in the smooth muscle of [email protected] cavernous bodies. It is found in the smooth muscle fibers of other vessels especially Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction Page 2 of 6 pulmonary. The effects of PDE5 inhibition on pulmonary arterial hypertension are under study. The effects on asthma are rather compared with placebo, sildenafil doses of up to 100 mg resulted in a statistically significant increase in the duration of erections related to PDE4 inhibitors, which are involved in bronchial with a degree of rigidity of 60% (stiffness commonly considered inflammationDifferent Drugs and contraction Used to ofTreat bronchial Erectile smooth Dysfunction muscle fibers sufficient for penetrating sex). In patients who responded to the drug, the median time between oral administration of 50 mg sildenafil and onset of erection (60% stiffness) in response to SSV The most commonly used PDE5 inhibitor drugs are sildenafil, was 25 minutes. The mean duration of erections with stiffness up to 60% at the base of the penis, in men who received placebo, 25 tovardenafil, achieve antadalafil, erection andand maintainavanafil this[8]. erectionThese medicationswhen there mg and 50 mg sildenafil, in combination with a 2-hour exposure isthemselves sexual stimulation. do not produce PDE5 inhibitorerections tabletsin men, have but noallow effect them in to SSV, was 3 minutes, 24 minutes and 32 minutes, respectively men with decreased libido and unable to produce a satisfactory [12,13].Pharmacokinetics erection. Sildenafil oralSildenafil administration is rapidly in fastedabsorbed. subjects. Peak Theplasma average concentration absolute is reached at 30 to 120 minutes (median: 60 minutes) after Sildenafil preferentially inhibits PDE5 and to a lesser extent bioavailability is 41% (range 25% to 63%). The pharmacokinetic PDE6 (retina) [9] while it has no effect on PDE3 (heart). In vitro proportional when the dose is within the recommended dose parameters of sildenafil, when administered orally, are dose studies indicate that sildenafil is only 10-fold more selective for PDE5 than PDE6, while it is 4000 times more selective for PDE5 range (25 mg to 100 mg). Taking Sildenafil at a high-fat meal than PDE3. Sildenafil has no direct muscle relaxant effect on resulted in a marked slowing of the drug’s absorption rate, which isolated tissue of the human cavernous body. Rather, it enhances resulted in an average Tmax prolongation of 60 minutes and an the effect of NO by inhibiting PDE5, the enzyme responsible for average reduction of 29 minutes. % of Cmax [14]. In concrete biodegradation of cGMP in cavernous bodies. During the local terms, this means that if the patient takes his medication with a release of NO following sexual stimulation, the inhibition of PDE5 high-fat meal, the effect will be longer. Furthermore, even though by sildenafil produces an increase in the concentration of cGMP the amount of drug absorbed was lower (11% decrease in AUC), in the corpora cavernosa, hence the relaxation of the smooth and this decrease was statistically significant, it was not of clinical muscles they contain and the influx of blood into the penis [10]. absence of sexual stimulation. In vitro studies have shown that significance. The relative bioavailability of the product taken with Sildenafil given at the recommended doses has no effect in the a meal rather than fasting was 89% (90% CI, 84 to 94%) sildenafil has an affinity 10 to 10 000 times greater for PDE5 than The mean steady-state volume of distribution of Sildenafil for other phosphodiesterase’s (including PDE1, PDE2, PDE3, in(Vd the eq) circulation is 105 liters, both indicating bind to plasma that theproteins product in approximatelyis distributed PDE4 and PDE6) and that it acts at least 700 times more on in the tissues. Sildenafil and its major N-desmethyl metabolite PDE5 than on PDE7 to 11. More precisely, the affinity of sildenafil for PDE5 is more than 4000 times higher than its affinity for the96%. sperm This ofparameter healthy volunteers is independent revealed of thatthe lesstotal than concentration 0.001% of PDE3, the cAMP-specific phosphodiesterase that participates at of the drug. Measurement of the amount of sildenafil present in the regulation of cardiac contractility. In addition, the effect of sildenafil is approximately 10 times more potent on PDE5 than the ingested dose may appear in the sperm of patients 90 minutes on PDE6, an isoenzyme found in the retina. This low affinity for after taking the drug. concentrationsPDE6 may explain of theabnormalities drug. in color discrimination observed Sildenafil is primarily removed from the body by two with high doses of sildenafil or in the presence of high plasma presentmicrosomal in the liver circulation isoenzymes, is formedCYP3A4 by (main N-demethylation metabolic pathway) of the and CYP2C9 (secondary metabolic pathway). The main metabolite PDE5 is also present in low levels in platelets, smooth vessels inhibitoryand viscera activity as well of nitric as in oxide skeletal on platelet muscles. aggregation The inhibition observed of actionN-methylpiperazine in vitro is equivalent part. The to approximatelymetabolite’s affinity 50% of for that PDEs of the is PDE5 by sildenafil in these tissues would explain the increased parentsimilar todrug. that Its of sildenafil,plasma concentration and the potency is about of its PDE540% inhibitoryof that of peripheral vasodilatation in vivo [11]. in vitro, inhibition of platelet thrombus formation in vivo and terminal half-life is approximately 4 hours. sildenafil. The N-demethyl derivative is also metabolized, and its In eight placebo-controlled, double-blind, placebo-controlled